A retrospective study published in Holistic Integrative Oncology reports that children with stage 4 neuroblastoma who had elevated levels of plasma catecholamines were more likely to achieve complete remission after receiving an induction chemotherapy regimen that included arsenic trioxide. The research, conducted at Sun Yat-sen Memorial Hospital in Guangzhou, China, analyzed data from 16 pediatric patients diagnosed between 2018 and 2020. The findings suggest a potential association between specific biochemical markers in the blood and therapeutic outcomes, although the authors emphasize that the small sample size limits the statistical power of the conclusions.
Neuroblastoma is the most common extracranial solid tumor in children, arising from the developing sympathetic nervous system. Because this tumor type originates from neural crest cells, it is intrinsically linked to the physiology of catecholamine production. While urinary catecholamine metabolites are a standard part of the diagnostic basis for neuroblastoma, the predictive value of plasma catecholamine concentrations for patient prognosis and their application in guiding therapeutic interventions had not been clearly confirmed prior to this analysis.
The study team aimed to reveal the potential clinical significance of a panel of plasma catecholamine metabolites in children with high-risk disease. All 16 patients enrolled in the study were diagnosed with stage 4 neuroblastoma according to the International Neuroblastoma Staging System criteria. The cohort consisted of seven males and nine females, with a median age of 4.1 years and an age range spanning from 0.4 to 13.6 years. Primary tumor sites were predominantly in the retroperitoneal and adrenal area for 15 patients, while one patient had a mediastinal tumor. The average diameter of the primary tumors was 7.7 cm, with a range of 2.7 to 13.1 cm.
Each patient received an innovative induction chemotherapy regimen that combined arsenic trioxide with a modified N7 induction protocol. The arsenic trioxide was administered intravenously at a dose of 0.16 mg/kg/day for 10 days per cycle, totaling nine cycles. This was combined with four cycles of the CAV regimen, three cycles of the PVP regimen, and two cycles of the CT regimen. Plasma samples were collected from peripheral venous blood at diagnosis and at the end of the induction phase. The samples were processed using high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry to measure specific metabolites.
The researchers measured six specific plasma catecholamine metabolites: dopamine, 3-methoxytyramine, norepinephrine, epinephrine, normetanephrine, and metanephrine. Hypercatecholaminemia was defined as an elevation of any of these metabolites above specific thresholds. For example, dopamine levels above 0.65 nmol/L or epinephrine levels above 0.55 nmol/L were considered elevated. In the cohort, six patients, representing 37.5% of the group, had elevated plasma catecholamine levels. Among these six, one child experienced both malignant hypertension and tachycardia, three children suffered only from tachycardia, and the remaining two children showed no adrenergic symptoms.
The analysis revealed significant correlations between plasma catecholamine levels and other clinical markers. Plasma dopamine levels were significantly associated with the urine vanillylmandelic acid-to-creatinine ratio, serum neuron-specific enolase, and tumor diameter. Similarly, plasma epinephrine levels showed positive correlations with these same markers. These associations suggest that higher levels of certain catecholamines in the plasma may reflect greater absolute tumor burden or specific metabolic profiles of the tumor cells. However, the study noted that the accuracy of urinary markers can be affected by various factors, such as food types and sample storage, which may make plasma measurements a more precise indicator of tumor metabolism.
After treatment, five patients achieved complete remission, seven attained partial remission, one exhibited no response, and three developed progressive disease. When comparing the complete remission group to the non-complete remission group, a statistically significant difference was observed in the incidence of hypercatecholaminemia. Four out of the five patients in the complete remission group had elevated catecholamine levels, whereas only two out of the 11 patients in the non-complete remission group did. This difference was statistically significant with a P-value of 0.036.
Specifically, the plasma dopamine level in the complete remission group was significantly higher than that in the non-complete remission group, with a P-value of 0.002. While plasma levels of other catecholamines were generally higher in the complete remission group, these differences did not reach statistical significance. The authors suggest that the unique inclusion of arsenic trioxide in the chemotherapy regimen may be related to these findings.
Long-term survival analysis was also conducted, with a median follow-up of 27 months. Exploratory Kaplan-Meier estimates indicated that the 5-year overall survival rate was 80% for patients with hypercatecholaminemia, compared to 51.4% for those without. The 5-year progression-free survival rate was 50% for the hypercatecholaminemia group and 17.5% for the non-hypercatecholaminemia group. Although patients with elevated catecholamines exhibited a trend toward improved survival outcomes, the differences were not statistically significant, with P-values of 0.577 for overall survival and 0.398 for progression-free survival.
The study acknowledges several limitations that must be considered when interpreting these results. The most significant limitation is the relatively small sample size of 16 patients, which limits the statistical power and precludes definitive conclusions. The absence of a concurrent control group that did not receive arsenic trioxide limits the ability to claim specificity for this particular drug. Furthermore, the retrospective nature of the analysis and the small cohort make it difficult to perform robust multivariate analyses to adjust for potential biases, such as age differences between the subgroups.
The authors conclude that catecholamine secretion and metabolism are heterogeneous in neuroblastoma patients, and that clinical symptoms of catecholamine excess are not invariably present. The findings suggest that patients with elevated plasma catecholamines, particularly those with increased dopamine levels, may have a more favorable response to chemotherapy regimens containing arsenic trioxide. However, these findings should be interpreted as preliminary and hypothesis-generating.
Future research is warranted to validate these clinical observations. The authors recommend further parallel-controlled studies with expanded sample sizes and mechanistic investigations to better understand the relationship between plasma catecholamine levels and therapeutic response in neuroblastoma. Such studies could help clarify whether plasma catecholamine measurements can be used as a biomarker to guide personalized therapeutic approaches for high-risk neuroblastoma patients.
The biological basis for this association lies in the specific cellular composition of neuroblastoma tumors. The source evidence indicates that most neuroblastomas contain two or three distinct types of tumor cells, characterized by adrenergic, mesenchymal, and stem cell-like phenotypes. The proportions of these different cell types may influence the clinical behavior of the tumor. The authors hypothesize that plasma catecholamine levels depend not only on the total tumor burden but also on the specific proportion of adrenergic cells within the tumor mass. This suggests that the biochemical profile of the blood may reflect the internal cellular architecture of the cancer, providing a window into its metabolic activity that is not captured by tumor size alone.
Catecholamine excretion patterns in neuroblastoma patients are heterogeneous, with different patients exhibiting distinct metabolic profiles. Previous research has described four profiles of catecholamine excretion, ranging from prominent elevations in dopamine and 3-methoxytyramine to patterns dominated by normetanephrine. In the current cohort, the metabolism of dopamine was not frequently blocked, which is a pattern previously associated with poorer outcomes in other studies. The heterogeneity observed in this study aligns with the broader understanding that neuroblastoma is a complex malignancy with variable biological behavior, where even patients receiving the same risk-based treatment can experience widely varying prognoses.
The clinical presentation of hypercatecholaminemia in this cohort was variable, with only two-thirds of the affected patients showing symptoms. The most common manifestation was tachycardia, observed in 66.7% of the hypercatecholaminemic patients, while hypertension was present in 16.7%. In all cases where tachycardia was present, the symptoms were alleviated by the administration of beta-1 receptor blockers, implying a hypercatecholamine-mediated mechanism. One patient experienced severe symptoms, including inappropriate sweating, shortness of breath, and severe hypertension, which required intravenous esmolol and other interventions. This patient also developed heart failure after the second chemotherapy cycle, which was relieved following primary tumor resection. The fact that some patients with elevated catecholamines remained asymptomatic highlights the complexity of interpreting biochemical markers in the absence of clinical signs.
The study’s findings contrast with previous reports that have consistently associated elevated urinary catecholamine metabolites, such as 3-methoxytyramine and vanillylmandelic acid, with aggressive disease and poor outcomes. In this research, while no significant differences were found in tumor diameter, serum neuron-specific enolase, or urinary vanillylmandelic acid-to-creatinine ratio between the hypercatecholaminemia and non-hypercatecholaminemia groups, positive correlations were observed between most catecholamine metabolites and these markers. This discrepancy may be attributed to the unique inclusion of arsenic trioxide in the chemotherapy regimen. Experimental evidence suggests that arsenic trioxide can inhibit the proliferation of neuroblastoma cells by retarding the cell cycle and has synergistic cytotoxic effects when combined with other chemotherapy drugs. The potential interaction between arsenic and dopamine pathways in neuroblastoma cells provides a plausible mechanistic link for the observed therapeutic response.
Subject of Research: Association between plasma catecholamine levels and chemotherapy response in pediatric neuroblastoma
Article Title: Elevated plasma catecholamines in neuroblastoma patients are associated with positive therapeutic response to chemotherapy regimen containing arsenic trioxide
Article References: Peng, X., Xiong, X., Wang, W., Wang, Z., Weng, W., & Li, Y. (2026). Elevated plasma catecholamines in neuroblastoma patients are associated with positive therapeutic response to chemotherapy regimen containing arsenic trioxide. Holistic Integrative Oncology, 5(1), Article 93. https://doi.org/10.1007/s44178-026-00310-8
Image Credits: AI Generated
DOI: 10.1007/s44178-026-00310-8
Keywords: neuroblastoma, catecholamines, arsenic trioxide, pediatric oncology, chemotherapy, biomarkers, retrospective study, dopamine, Elevated, plasma, patients, associated
News Source: Nathaniel Bowman. (November 10, 2026). High Plasma Catecholamines Linked to Better Neuroblastoma Response. Scienmag.
